USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer

Pingping Hou, Xingdi Ma, Zecheng Yang, Qiang Zhang, Chang Jiun Wu, Jun Li, Lin Tan, Wantong Yao, Liang Yan, Xin Zhou, Alec C. Kimmelman, Philip L. Lorenzi, Jianhua Zhang, Shan Jiang, Denise Spring, Y. Alan Wang, Ronald A. DePinho

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Activating mutations in KRAS (KRAS) are present in nearly all pancreatic ductal adenocarcinoma (PDAC) cases and critical for tumor maintenance. By using an inducible KRAS PDAC mouse model, we identified a deubiquitinase USP21-driven resistance mechanism to anti-KRAS therapy. USP21 promotes KRAS-independent tumor growth via its regulation of MARK3-induced macropinocytosis, which serves to maintain intracellular amino acid levels for anabolic growth. The USP21-mediated KRAS bypass, coupled with the frequent amplification of USP21 in human PDAC tumors, encourages the assessment of USP21 as a novel drug target as well as a potential parameter that may affect responsiveness to emergent anti-KRAS therapy.

Original languageEnglish (US)
Pages (from-to)1327-1332
Number of pages6
JournalGenes and Development
Volume35
Issue number19
DOIs
StatePublished - Oct 1 2021
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

Keywords

  • KRAS
  • MARK3
  • Macropinocytosis
  • Targeted therapy resistance]
  • USP21

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